Sleep apnea is a systematic disorder. All tissues in the body experience hypoxia that occurs as a consequence of apneas. Thus, sleep apnea leads to multiple adverse consequences. Sleep apnea is heritable, although to date no convincing gene variants have been identified. There are also important individual differences in risks and consequences within patients. These individual differences suggest that sleep apnea is an ideal disorder to develop a PERSONALIZED approach to risk assessment, diagnosis and management. It is this overall concept that motivates this program of research. The program has 3 projects and 5 supporting cores. The first project-Mechanisms of Extreme Phenotypes in Obstructive Sleep Apnea (OSA) (Project Leader: R. Schwab)-is focused on understanding the basis of extreme phenotypes. In this project the investigators study very obese individuals with and without sleep apnea. They ask the question-given that these individuals have the major risk for sleep apnea, what protects those without the disorder? Is it a difference in fat distribution, different physiological control mechanisms or a combination? The investigators also study lean individuals with and without sleep apnea and ask the same question-why? What role does craniofacial structure, different distributions of fat and ventilatory control system instablity play in the development of apnea in thin individuals? This project is based on in-depth phenotyping. Project 02-Mechanisms for Individual Differences in Hypertension in Obstructive Sleep Apnea (Project Leader: S. Kuna)-addresses the basis of individual differences in blood pressure response to sleep apnea. The investigators propose that the largest effect of sleep apnea on blood pressure will occur in individuals whose BP is not controlled on anti-hypertensive medications, and that these individuals will benefit most from PAP treatment. They ask the question-why? The investigators propose that the individual differences in blood pressure response are related to individual differences in oxidative stress and catecholamine responses to sleep apnea. They predict that these proposed mediators are driven by genetic differences in the key enzyme that leads to oxidative stress-NADPH oxidase-and propose sequencing of genes that regulate activity of this enzyme. The final project-Genetics of Sleep Apnea and Its Consequences (Project Leader: A. Pack)-continues the genetic theme, but proposes a new strategy to identify genes conferring risk for sleep apnea and its consequences. This strategy involves mice, in particular the genetically heterogeneous Diversity Outbred mice, a recently developed, state-of-the-art approach to genetic discovery through animal models that has already shown its ability to discover new genetic associations. High throughput phenotyping of these mice, together with genotyping with a genome-wide SNP chip, allows identification of small genomic regions that relate to the phenotype being studied. The phenotypes being assessed in Project 03 are: tongue fat (relevant to anatomy in Project 01), ventilatory responses to hypoxia/hypercapnia (related to physiological mechanisms in Project 01), and blood pressure response to cyclical intermittent hypoxia, akin to that which occurs in sleep apnea (relevant to Project 02). Thus all 3 projects work synergistically. All projects are supported by 5 cores: a) Administrative, b) Sleep Study and Recruitment, c) Magnetic Resonance Imaging, d) Molecular Assessment, and e) Biostatistics and Data Management.